Parathyroid Hormone

Overview

Parathyroid hormone (PTH) is an 84-amino acid polypeptide secreted by the parathyroid glands that serves as the primary regulator of calcium and phosphorus homeostasis. First characterized in the early 20th century and structurally elucidated by Potts and colleagues, PTH acts on bone and kidney to maintain serum calcium within a narrow physiological range. The N-terminal fragment PTH(1-34) retains full biological activity and is the basis for therapeutic agents.

Structure and Biosynthesis

PTH is synthesized as a 115-amino acid prepropeptide. After signal peptide removal, the 91-residue pro-PTH is cleaved by furin-like proteases to yield the mature 84-residue hormone. The active site resides in the N-terminal 34 residues, which form two alpha-helical segments connected by a flexible hinge region. The C-terminal region (residues 35-84) lacks classical receptor activity but modulates calcium metabolism through receptor-independent mechanisms and may interact with the G-protein-coupled receptor GPRC6A.

Receptor and Signaling

PTH binds the PTH1 receptor (PTH1R), a class B G-protein-coupled receptor that also recognizes PTH-related peptide (PTHrP). The receptor signals through both Gs (cAMP/PKA) and Gq/11 (PLC/calcium) pathways, with distinct biological outcomes depending on the signaling mode. Intermittent PTH exposure activates anabolic bone formation through Wnt/beta-catenin signaling, whereas continuous PTH exposure promotes bone resorption via RANKL upregulation. The PTH2 receptor (PTH2R) is expressed predominantly in the CNS and binds tuberoinfundibular peptide (TIP39).

Physiological Actions

PTH increases serum calcium by stimulating osteoclast-mediated bone resorption, enhancing renal calcium reabsorption in the distal tubule, and promoting intestinal calcium absorption indirectly through stimulation of 1,25-dihydroxyvitamin D synthesis. PTH simultaneously reduces renal phosphate reabsorption (phosphaturia) through downregulation of sodium-phosphate cotransporters. In bone, intermittent PTH activates osteoblast differentiation and suppresses osteoblast apoptosis.

Therapeutic Applications

Teriparatide (recombinant PTH(1-34)) is an approved anabolic therapy for osteoporosis and glucocorticoid-induced osteoporosis. Intermittent subcutaneous administration stimulates new bone formation, reducing vertebral and non-vertebral fracture risk. Abaloparatide (PTHrP(1-34) analog) and romosozumab (anti-sclerostin antibody) represent complementary anabolic approaches. Recombinant PTH(1-84) is approved for hypoparathyroidism. PTH mutations cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism.